Cefditoren is a cephem compound represented by the following formula (A): ##STR1## and named as (+)-(6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3-(Z) -2-(4-methylthiazol-5-yl)-ethenyl!-8-oxo-5-thia-1-azabicyclo4.2.0!oct-2-en e-2-carboxylic acid. This cephem compound having the generic name "Cefditoren" is also nominated as 7-2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido!-3-2-(4-methylthiazol- 5-yl)vinyl!-3-cephem-4-carboxylic acid(syn-isomer, cis-isomer) in the specifications of Japanese patent No. 1698887(Japanese patent publication "Kokoku" No. Hei-3-64503 published on Oct. 7, 1991), U.S. Patent No. 4,839,350 and European patent No. 0175610. A pivaloyloxymethyl ester of Cefditoren, where the 2-carboxyl group of said cephem compound has been esterified with pivaloyloxymethyl group for the purpose of enhancing the absorbability of the cephem compound via the digestive tubes upon the oral administration thereof (the absorbability of the cephem compound in this sense is referred to simply as "oral absorbability" sometime hereinafter),is such a pro-drug which is known under a generic name "Cefditoren pivoxyl". This pro-drug compound is represented by the following formula (B): ##STR2## and has a chemical name "(-)-(6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3-(Z )-2-(4-methylthiazol-5-yl)ethenyl!-8-oxo-5-thia-1-azabicyclo4.2.0! oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyloxymethyl ester".
It is generally deemed that when such a medicinal compound (called simply as a drug hereinafter) which is essentially in the form of an acid has been esterified at the acid group thereof with an ester-forming group, the resulting ester compound can gain an enhanced or improved lipophilicity through the esterification so as to increase the membrane permeability of the drug at the digestive tubes, whereby the resulting ester compound can attain an enhancement in its absorbability at the digestive tubes, namely an enhanced oral absorbability much than that of the original drug of the acid form. As be known well, however, the absorbability of a drug at the digestive tubes is closely co-related to the solubility of said drug in water. The esterified drug, owing to its enhanced lipophilicity, can have its reduced characteristics that relate to the solubilities of the drug in respect of its wettability with water, its dispersibility in water, and others. Therefore, some problems have occurred in that the esterification of a medicinal compound is not necessarily able to achieve an enhancement or improvement in the absorbability of the compound at digestive tubes to a satisfactory extent.
Cefditoren, which is the antibacterially active species, does not exhibit the bitter taste by itself upon oral administration thereof, whilst Cefditoren pivoxyl of the ester form is the pro-drug which can exhibit a strong bitter taste objectionably to patients who receive oral administration of it. Thus, there is a strong demand that the bitter taste of Cefditoren pivoxyl is to be reduced or minimized to such an extent that the oral administration of Cefditoren pivoxyl would be acceptable by patients. On the other hand, to solve certain problems concerning the oral absorbability of Cefditoren pivoxyl, there has been proposed several years ago such a formulation in which Cefditoren pivoxyl is mixed with a cyclodextrin or a hydroxypropyl cellulose, one of water-soluble cellulose derivatives of high molecular weights (Japanese patent application first publication "Kokai" Nos. Hei-1-268637 and Hei-7-17866). However, the addition of cyclodextrin to Cefditoren pivoxyl can bring about the formation of a water-soluble complex of Cefditoren pivoxyl with cyclodextrin, with involving a great increase in the solubility of Cefditoren pivoxyl itself in water and thereby enhancing highly the bitter taste which is attributable just to the drug, Cefditoren pivoxyl. The highly enhanced bitter taste of this drug which is brought about by the addition of cyclodextrin can lead to a great trouble to patients who receive oral administration of the above-mentioned formulation comprising the mixture of Cefditoren pivoxyl with cyclodextrin.
While, in order to improve the oral absorbability of Cefditoren pivoxyl by the addition of hydroxypropyl cellulose thereto, it is necessary that the amount of hydroxypropyl cellulose as added to and mixed with Cefditoren pivoxyl is increased considerably much more than such usual amounts of hydroxypropyl cellulose which was conventionally used as a binding agent in an amount of 1% by weight or more or less on the basis of the weight of the whole formulation comprising Cefditoren pivoxyl and the hydroxypropyl cellulose added as the conventional binding agent. When a considerably increased amount of hydroxypropyl cellulose has been added to and mixed with Cefditoren pivoxyl, the function of the added hydroxypropyl cellulose to act as the binding agent can display strongly.
In order to suppress the strong binder-function of the hydroxypropyl cellulose as incoporated in said considerably increased amount, it is necessary to also increase considerably the amount of a disintegrator to be added to Cefditoren pivoxyl, so that the disintegratability of the tablet preparation or granule preparation as formulated therefrom can be kept at a reasonable degree. This necessity would lead to another problems such that the resulting tablet preparation or granule preparation should be of a bulky volume and should be difficult to be taken by patients orally. Besides, the addition of hydroxypropyl cellulose to Cefditoren pivoxyl can bring about a problem such that the water component present in the preparations comprising the mixture of Cefditoren pivoxyl with hydroxypropyl cellulose is difficult to be removed therefrom and hence the water content of said preparations cannot be minimized, so that the water content can disadvantageously result in a possible decrease in the stability of the active drug component present in said preparations. Furthermore, the method of mixing Cefditoren pivoxyl with hydroxypropyl cellulose is essentially not able to reduce the bitter taste of Cefditoren pivoxyl itself to a satisfactorily full extent.
Whilst, various methods for masking or reducing the bitter taste of medicinal compositions or formulations containing a drug compound having a bitter taste are generally known hitherto. For instance, the known methods of masking the bitter taste of a drug compound embraces a method of coating the surfaces of the particles of the drug compound with a coat-film. This method of coating the particle surfaces of the drug compound with the coat-film can suitably be applied to the preparations of the tablet form. However, when this method is effected for the preparations of the granule form or the fine granule form, there can be involved such drawbacks that the surfaces of the granules or the fine granules so coated become rough and give objectionable feelings to mouth and tongue, and that the steps for the production of the granules or the fine granules so coated with the film are complicated, and so on. A method of mixing a sweetening agent or a flavoring agent with the drug having a bitter taste may also be employed, but this method is not effective to a sufficient extent. Accordingly, there remains now an outstanding demand to provide a new and much more effective measure for solving the problems that the bitter taste of a drug having a bitter taste should be reduced or minimized to an extent acceptable to patients.